Over the last decade, a large body of evidence has established that obesity is associated with a worse breast cancer prognosis for both pre- and postmenopausal women. There are several mechanism(s) which have been proposed for promoting this effect, with recent evidence suggesting that the obese state is associated with changes in the biology of the disease, promoting a more aggressive phenotype. Clinically, obesity correlates with worse outcome on hormone therapy agents, most notably aromatase inhibitors (AI). Our group, as well as others, has demonstrated that obesity promotes increased local aromatase expression in the mammary gland. Our preliminary studies suggest that this induction is mediated primarily through cyclooxygenase (Cox)-derived prostaglandin E2 (PGE2), that this induction is associated with increased estrogen receptor ? (ER?) activity in mammary epithelial cancer cells, and most importantly, that regular use of NSAIDs may reduce the rate of recurrence on AIs by half. These data suggest that interventions that suppress COX-2 PGE2 production may provide significant benefit for the obese ER+ patient. Omega-3 fatty acids have demonstrated anti-cancer benefit through multiple mechanisms, including suppression of inflammation-related signaling. The omega-3 PUFAs serve as competitive substrates for COX- 2 activity, resulting in suppressed PGE2 production. Importantly, our preliminary data suggest that at physiological relevant levels DHA is able to inhibit obesity-induced PGE2 production in vitro. Our exceptional collaborative team of investigators will use highly integrated pre-clinical and clinical studies to test the novel hypothesis that omega-3 fatty acid supplementation can be used to improve response to AIs in the obese postmenopausal breast cancer patient population and prevent many of the tumor-promoting effects of obesity. The results of this study could have an immediate impact on patient outcomes by transitioning directly into a larger intervention trial evaluating both the proposed mechanism of resistance and the use of omega-3 fatty acid supplements to improve response.